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Smith-Lemli-Opitz syndrome

MIM.270400 11q12-q13

Tuesday 25 November 2003

Definition: Smith-Lemli-Opitz syndrome (SLO) is characterised by pre- and postnatal growth retardation and microcephaly, severe mental retardation, facial dysmorphic features, hypospadias and syndactyly between toes 2 and 3.

SLO results from cholesterol metabolic impairment with mutation of the 7-dehydro-cholesterol reductase gene (DHCR7, chromosome 11q12-q13).

SLOS patients have decreased cholesterol and increased 7-dehydrocholesterol (7-DHC) levels.

Dietary cholesterol supplementation improves systemic biochemical abnormalities; however, because of the blood-brain barrier, the central nervous system (CNS) is not treated. Simvastatin therapy has been proposed as a means to treat the CNS.


- systemic anomalies

  • short stature
  • developmental delay
  • intrauterine growth retardation (IUGR)
  • postnatal growth retardation
  • birth weight @<@2500gm
  • failure to thrive
  • decreased fetal movement
  • breech presentation

- craniofacial anomalies

- cardiovascular anomalies (12797454)

- pulmonary anomalies

  • hypoplastic lungs
  • incomplete lobulation of the lungs

- gastrointestinal anomalies

- atypical mononuclear giant cells in pancreatic islets

- genital anomalies

- urinary anomalies

- limb anomalies

  • postaxial polydactyly
  • hand syndactyly
  • proximally placed thumbs
  • syndactyly of second and third toes
  • talipes calcaneovalgus
  • short, broad toes
  • overriding toes
  • metatarsus adductus

- cutaneous anomalies

- central nervous system

  • hydrocephalus (dilated ventricles)
  • microcephaly
  • frontal lobe hypoplasia
  • cerebellar hypoplasia
  • brainstem hypoplasia
  • gray matter periventricular heterotopia
  • irregular gyral pattern
  • irregular neuronal organization
  • anomalies of spinal cord development


- low cholesterol
- elevated 7-dehydrocholesterol

Phenotypic variants

- lethal form of SLOS: Rutledge multiple congenital anomaly syndrome (RMCAS) (SLO2) (Ex-MIM.268670) (12717589)


Smith-Lemli-Opitz syndrome is a autosomal recessive malformative syndrome caused by mutations in the sterol delta-7-reductase gene (DHCR7) (MIM.602858), which maps to 11q12-q13.

- mutations in the gene DHCR7 encoding sterol delta-7-reductase at 11q12-q13 (MIM.602858)


The Smith-Lemli-Opitz syndrome (SLOS; MIM.270400) is the prototypical example of a human malformation syndrome resulting from an inborn error of cholesterol synthesis. It was first described in 1964.

Smith, Lemli, and Opitz initially described three male patients with similar facial features, mental retardation, microcephaly, developmental delay, and hypospadias, and they designated the novel disorder as the RSH syndrome, referring to the names of the first three patients.

In various populations, the clinical incidence of this condition has been reported to range from 1 in 10,000 to 1 in 60,000, although SLOS is thought to be more common in individuals of Northern European descent.

SLOS, along with a severe variant (type II SLOS, or Rutledge lethal multiple congenital anomaly syndrome; MIM.268670), is now known to represent a single, clinically heterogeneous genetic disorder.

Infants at the severe end of the SLOS phenotypic spectrum often die due to multiple major congenital anomalies.

Conversely, individuals at the mild end of the spectrum show only minor physical stigmata, coupled with behavioral problems that can include aspects of autism and self-injurious behavior. Although near-normal intelligence has been reported, moderate to severe mental retardation is typical.

The classical SLOS face is distinctive: Typical craniofacial features include microcephaly, metopic prominence, ptosis, a small upturned nose, cleft palate, broad alveolar ridges, and micrognathia, with cataracts developing pre- or postnatally.

Limb abnormalities are frequent in SLOS, and syndactyly of the second and third toes is the most frequent single physical finding.

Because the SLOS phenotypic spectrum is so broad, the presence of second-third toe syndactyly in a child with significant mental or behavioral problems should prompt consideration of SLOS.

Other limb anomalies include short and proximally placed thumbs, single palmar creases, and postaxial polydactyly of either the upper or lower extremities. Congenital heart defects are common. Slow growth and poor weight gain are typical. Most SLOS infants are poor feeders, and gastrostomy tube placement is required in many cases. Gastrointestinal anomalies include colonic aganglionosis, pyloric stenosis, and malrotation. Genital malformations are common in male patients. Hypospadias is a typical finding, and more severely affected patients may have ambiguous genitalia.

In 1993, Irons and coworkers reported decreased serum levels of cholesterol and elevated levels of 7-dehydrocholesterol (7-DHC) in two SLOS patients. The conversion of 7-DHC to cholesterol, the last enzymatic reaction in the Kandutsch-Russel cholesterol synthetic pathway, is catalyzed by the 3β-hydroxysterol Δ7-reductase.

In 1998, three groups, including ours, independently cloned the human 3β-hydroxysterol Δ7-reductase gene (DHCR7), which encodes this enzyme, and identified DHCR7 mutations in SLOS patients.

The DHCR7 protein is predicted to be a 475–amino acid polypeptide integral membrane protein with up to nine transmembrane domains. To date, 79 SLOS disease alleles have been identified in DHCR7, the most frequent of which is IVS8-1G→C (32%).

This splice acceptor mutation, which results in the inclusion of 134 bp of intronic sequence in the DHCR7 mRNA, is a null allele, and IVS8-1G→C homozygotes typically have a severe phenotype. Other relatively common alleles include T93M (9%), W151X (7%), V326L (6%), R404C (5%), and R352W (3%).

Establishing a genotype/phenotype correlation for SLOS has been confounded by the large number of different alleles and the fact that most patients are compound heterozygotes.

The observation that patients with the same DHCR7 genotype may have markedly different phenotypic severity suggests that other genetic, developmental, or maternal factors, perhaps affecting cholesterol biosynthesis or homeostasis, significantly influence a given patient’s phenotype.

The IVS8-1G→C allele has been reported to have a carrier frequency of 1.06% (16 in 1,503) in an Oregon population. A 1% carrier frequency for the IVS8-1G→C mutation predicts an IVS8-1G→C homozygosity incidence of 1 in 40,000.

Since the IVS8-1G→C mutation accounts for a third of the ascertained mutant DHCR7 alleles, this finding has been used to predict carrier frequencies of 1 in 30 and disease incidences on the order of 1 in 1,590 to 1 in 13,500.

This predicted disease incidence is much higher than clinical data would indicate, suggesting that a substantial number of severely affected fetuses with two severe alleles may be lost prenatally.

An alternative explanation, that not all SLOS patients are currently being ascertained, could be addressed in a newborn screening trial. Indeed, given the availability of a therapeutic intervention, such a screen should be considered.

The high carrier frequency of the IVS8-1G→C mutation has led to speculation that heterozygotes are at a competitive advantage. Decreased cardiac or thromboembolic disease has been proposed as a possible advantage but seems unlikely, since these disorders usually affect individuals after their reproductive years.

However, since many viruses rely on a membrane fusion event to infect cells, it is plausible that the presence of low levels of 7-DHC in the plasma membrane could protect the host from some viral diseases, a possibility that has yet to be tested in mouse models or human cell lines.

In addition, since 7-DHC in the skin is the precursor for vitamin D synthesis, increased 7-DHC levels in heterozygotes could be adaptive in a Northern European population at risk of vitamin D–deficient rickets.

Dietary cholesterol supplementation has been attempted in SLOS, but the efficacy of this approach is probably limited by inefficient cholesterol transport across the blood-brain barrier and by the inability to reverse prior developmental effects of cholesterol deprivation.

Biochemically, cholesterol supplementation leads to an improved plasma cholesterol/total sterol ratio, and prolonged therapy can even decrease plasma 7-DHC levels.

Observational studies have reported multiple benefits of dietary cholesterol supplementation, including improved nutrition and growth, improved muscle tone and strength, decreased photosensitivity, decreased irritability, decreased tactile defensiveness, increased sociability and alertness, decreased self-injurious behavior, and decreased aggressiveness.

To date, a controlled, blinded trial of dietary cholesterol supplementation confirming these observations has not been published.

In a preliminary statement on one blinded trial, Kelley reported that he found no difference between supplementation with 50 mg/kg/d and with 150 mg/kg/d. Since 50 mg/kg/d exceeds daily cholesterol needs in children, the clinical effect may already be maximal at this dose.

Although dietary cholesterol supplementation has no effect on fixed developmental malformations, it does appear to improve the overall health status of these patients and to lessen the behavioral problems associated with this disorder.

Other treatment modalities have been considered as well. Bile acid supplementation has not shown a clear benefit. Fresh frozen plasma, a source of lipoproteins containing cholesterol, has been used for prenatal therapy and appears to be efficacious in the acute management of ill SLOS patients.

Inhibition of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, has been suggested as a means to reduce any toxic effects of 7-DHC. However, in a teratogenic rat model of SLOS, one inhibitor of this enzyme decreased cholesterol levels without decreasing 7-DHC levels.

This animal study, combined with prior evidence that these drugs can precipitate an acute metabolic crisis in mevalonic aciduria patients and with anecdotal reports of poor outcomes in SLOS patients treated with HMG-CoA reductase inhibitors, led to the concern that inhibition of endogenous cholesterol synthesis in SLOS could be detrimental.

Nevertheless, one small trial of simvastatin therapy in SLOS has been reported. Jira et al. treated two SLOS patients with simvastatin, and they reported decreased dehydrocholesterol levels, improved serum dehydrocholesterol/cholesterol ratios in serum and cerebral spinal fluid (CSF), and improved growth.

Curiously, they also observed a paradoxical increase in plasma cholesterol levels. This surprising finding might be explained by upregulation of the mutant DHCR7.

Because statins induce transcription of HMG-CoA reductase and many genes involved in cholesterol synthesis are coordinately regulated, simvastatin treatment may well have induced the synthesis of the 3β-hydroxysterol Δ7-reductase protein in these patients.

If a mutant allele encodes a protein with residual enzymatic function, such an increase in protein levels could result in increased conversion of 7-DHC to cholesterol.

Conversely, simvastatin upregulation of a null allele would clearly not increase the conversion of 7-DHC to cholesterol, but it could inhibit the endogenous sterol synthesis. Since 7-DHC appears to substitute for cholesterol in some cellular functions, the net effect of this situation may be detrimental.

Defining the mechanism of action of the HMG-CoA reductase inhibitors in SLOS will be important for safely designing a clinical trial. If upregulation of a partially functioning enzyme is the mechanism of the observed effect, initial trials should be limited to patients who can be demonstrated to have significant residual enzymatic function.

Since simvastatin crosses the blood-brain barrier, it may directly affect the biochemical defect in the CNS and thus, perhaps, the behavioral phenotype of the disease.

Several pharmacological inhibitors of 3β-hydroxysterol Δ7-reductase have been used in studies of SLOS teratogenesis.

However, these studies are confounded by the effects of these drugs on maternal cholesterol synthesis and on other enzymes involved in cholesterol biosynthesis.

Wassif et al. produced a genetic mouse model of SLOS by disruption of Dhcr7. As found in human patients, Dhcr7–/– pups have markedly reduced tissue cholesterol levels and increased 7-DHC levels.

Phenotypic overlap between this mouse model and the human syndrome includes intrauterine growth retardation; variable craniofacial malformations, including cleft palate; poor feeding with an abnormal suck; and neurological abnormalities, including apparent hypotonia, apparent weakness, and decreased movement.

See also

- defect of cholesterol biosynthesis


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- Singer LP, Marion RW, Li JK. Limb deficiency in an infant with Smith-Lemli-Opitz syndrome. Am J Med Genet. 1989 Mar;32(3):380-3. PMID: 2729358